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Sustained attention and vigilance deficits associated with HIV and a history of methamphetamine dependence
Running title: Sustained attention and vigilance deficits in HIV and methamphetamine
dependence Nina Pocucaa, Jared W. Young a,b, David A. MacQueen a,b, Scott Letendrea, Robert K. Heatona, Mark A. Geyera,b, William Perrya, Igor Granta, Arpi Minassiana,c, and the Translational Methamphetamine AIDS Research Center (TMARC) a Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804 b Desert-Pacific Mental Illness Research Education and Clinical Center, VA San Diego Healthcare System, San Diego, CA c VA Center of Excellence for Stress and Mental Health, Veterans Administration San Diego HealthCare System, 3350 La Jolla Village Drive, San Diego CA, 92161 *Correspondence: Nina Pocuca, Ph.D. Department of Psychiatry University of California San Diego 9500 Gilman Drive MC 0804 La Jolla, California 92093-0804 e-mail: [email protected]
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Abstract
Background: Human immunodeficiency virus (HIV)-associated neurocognitive disorders persist
in the era of antiretroviral therapy (ART). One factor that is elevated among persons with HIV
(PWH) and independently associated with neurocognitive impairment is methamphetamine
dependence (METH+). Such dependence may further increase cognitive impairment among
PWH, by delaying HIV diagnosis (and thus, ART initiation), which has been posited to account
for persistent cognitive impairment among PWH, despite subsequent treatment-related viral load
suppression (VLS; <50 copies of the virus per milliliter in plasma or cerebrospinal fluid). This
study examined the independent and combined (additive versus synergistic) effects of HIV and
history of METH+ on the sustained attention and vigilance cognitive domain, while controlling
for VLS. Methods: Participants included 205 (median age=44 years; 77% males; HIV-/METH-
n=67; HIV+/METH - n=49; HIV-/METH+ n=36; HIV+/METH+ n=53) individuals enrolled in
the Translational Methamphetamine AIDS Research Center, who completed Conners’ and the 5-
Choice continuous performance tests (CPTs). Results: METH+ participants exhibited deficits in
sustained attention and vigilance; however, these effects were not significant after excluding
participants who had a positive urine toxicology screen for methamphetamine. Controlling for
VLS, PWH did not have worse sustained attention and vigilance, but consistently displayed
slower reaction times across blocks, relative to HIV- participants. There was no HIV x METH
interaction on sustained attention and vigilance. Conclusions: Recent methamphetamine use
among METH+ people and detectable viral loads are detrimental to sustained attention and
vigilance. These findings highlight the need for prompt diagnosis of HIV and initiation of ART,
and METH use interventions.
Keywords: human immunodeficiency virus; methamphetamine; sustained attention; vigilance; continuous performance test
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Sustained attention and vigilance deficits associated with HIV and a history of methamphetamine
dependence
1. Introduction
Modern antiretroviral therapy (ART) has changed human immunodeficiency virus (HIV)
from life-threatening illness to chronic disease (Deeks et al., 2013). While ART has also
decreased incidence of HIV-associated dementia (Heaton et al., 2011), HIV-associated
neurocognitive disorders (HAND) persist (Antinori et al., 2007; Walker & Brown, 2018). Up to
half of people with HIV (PWH) present with milder neurocognitive impairment (Heaton et al.,
2010). Thus, research should identify how other risk factors prevalent among PWH, including
substance use (Dawson-Rose et al., 2017), affect cognitive dysfunction.
Methamphetamine (METH) use and METH dependence (METH+) are prevalent among
PWH (Cohen et al., 2016; Dawson-Rose et al., 2017; Hartzler et al., 2017). While amphetamines
improve cognitive function among amphetamine-naïve (MacQueen, Minassian, Henry, et al.,
2018; Smith & Farah, 2011) and some clinical samples (e.g., attention-deficit/ hyperactivity
disorder (ADHD; Baroni & Castellanos, 2015; Sagvolden & Xu, 2008), METH+ has been linked
to neurocognitive impairment (Potvin et al., 2018). METH use is also linked to poorer ART
adherence among PWH (Moore et al., 2012; Parsons et al., 2013; Passaro et al., 2015), leading to
detectable viral loads which are associated with cognitive decline (Heaton et al., 2015).
Conversely, viral load suppression (VLS) is associated with stable cognitive function over time
(Sanford et al., 2018).
METH+ is also associated with delayed HIV diagnosis and ART initiation (Kuchinad et
al., 2016; Passaro et al., 2015), leading to early and more severe immunosuppression.
Immunosuppression potentially drives irreversible CNS injury involving frontal systems,
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resulting in enduring cognitive impairments, that persist despite subsequent VLS (Heaton et al.,
2010; Heaton et al., 2011; Muñoz-Moreno et al., 2008). Thus, HIV+/METH+ persons may be at
greatest risk of cognitive impairment. Indeed, research points to the combined, deleterious
effects of HIV and METH on cognitive function, although it is unclear whether these effects are
additive or synergistic in nature (Norman & Basso, 2015; Soontornniyomkij et al., 2016).
Differentiating between the additive versus synergistic HIV and METH effects on cognitive
function would aid clinicians in selecting appropriate treatments (Brew & McArthur, 2019).
One cognitive function disrupted in PWH and METH+, is sustained attention and
vigilance (i.e., the ability to maintain concentration and consistently respond to stimuli; Levine et
al., 2008; London et al., 2005; Moran et al., 2014; Moran et al., 2019; Morgan et al., 2014;
Potvin et al., 2018). Sustained attention and vigilance underlie other cognitive functions (e.g.,
learning; Fortenbaugh et al., 2017) and implicated in ART adherence (Hinkin et al., 2002).
Research has yet to determine how METH+ affects sustained attention and vigilance in PWH.
Using Conners’ continuous performance test (CPT; Conners et al., 2000), Levine et al. (2006)
found that cocaine and amphetamine (stimulants that share pharmacological similarities with
METH) are associated with poorer sustained attention and vigilance, among PWH. The absence
of an HIV-negative (HIV-) group in Levine et al. (2006) precludes inferences regarding the
additive versus synergistic effects of HIV and stimulants on sustained attention and vigilance.
Further, although a valid and reliable measure (Egeland & Kovalik-Gran, 2010), Conners’ CPT
has not been adapted for use in non-humans, precluding the utilization of preclinical studies to
determine mechanistic underpinnings of observed deficits (Young et al., 2009). Such studies are
difficult to conduct with human participants (Markou et al., 2009).
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Ultimately, research is needed to determine the nature of HIV and METH effects on
sustained attention (Brew & McArthur, 2019), using a validated, cross-species measure such as
the 5-choice CPT (5C-CPT; Barnes et al., 2012; MacQueen, Minassian, Kenton et al., 2018;
Young et al., 2009; Young et al., 2013; Young et al., 2017; Young et al., 2019; Young et al.,
2020). Thus, this study evaluated the additive versus synergistic effects of HIV and METH on
sustained attention and vigilance, controlling for VLS. It was hypothesized that HIV and METH
would have a synergistic deleterious effect on sustained attention and vigilance in PWH.
2. Material and methods
2.1. Participants
Participants were drawn from the Translational Methamphetamine AIDS Research
Center (TMARC), an interdisciplinary research program examining HIV and METH+ effects on
neurocognitive function. This study used data from 205 participants who completed Conners’
and 5C-CPT (18-87 years, median age=44; see Table 1 for participant characteristics). Most
PWH were male (n=97, 95%), consistent with the gender distribution of HIV infection in
California (California Department of Public Health, 2019).
2.2. Procedures
Participants were recruited from the community, HIV clinics, and substance use
treatment programs in San Diego if they: (1) were aged >18 years; (2) met DSM-IV criteria for
METH+: (i) in the past 18 months, or (ii) in their lifetime, and met one DSM-IV abuse criterion
in the past 18 months; or (3) had no history of METH use disorder. Participants with a head
injury with loss of consciousness >30 minutes, or a medical, serious psychiatric or neurological
condition not associated with HIV and linked to neurocognitive deficits (e.g., Hepatitis C
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infection), or who met past 12-month DSM-IV dependence criteria for another substance
(excluding nicotine), were excluded.
Participants provided informed consent and were assessed between 2014 and 2019.
Participants provided demographic and substance use information. The Composite International
Diagnostic Interview (CIDI) assessed substance use disorders, while the Diagnostic Interview
Schedule for DSM-IV (DIS) assessed mental health disorders. Participants underwent a blood
test to confirm HIV status and examine plasma viral loads. ART use and nadir CD4 count
information were also collected. Participants were not provided with explicit instructions to
abstain from substances, however, they completed a urine toxicology screen prior to cognitive
testing, which included 5C-CPT and Conners’ CPT. Participants were reimbursed for their time.
Procedures were approved by the university Institutional Review Board.
2.3. Cognitive Tasks
Cognitive tasks were presented on a 56cm CRT Dell PC computer screen (60cm from
participant), using E-Prime2 software (Psychology Software Tools, 2012) for stimulus
presentation and data acquisition.
2.3.1. 5C-CPT
Participants responded using an arcade joystick that returned to center after each
response. Trials consisted of target (single circle) or non-target (five circles) stimuli that
appeared for 100ms, behind and arc of 5 lines. Participants were able to respond for <1s after the
stimuli disappeared (limited hold). Trials were separated by 0.5, 1, or 1.5s inter-trial interval
(ITI), programmed in a quasi-random manner so the same ITI did not appear in more than 3
consecutive trials. Participants completed 12 practice trials (10 target, 2 non-target) to
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demonstrate understanding of task instructions, before completing the task (225 target and 45
non-target trials).
Responding to target stimuli in the indicated direction was recorded as a hit. Inhibiting
responses to non-target stimuli was a correct rejection. Failure to respond to a target was an
omission, while responding to a location other than the circle was registered as incorrect. Failure
to inhibit responding during non-target trials resulted in a false alarm (FA). Responding before
stimuli appeared was a premature response (PR). Outcomes were calculated from these measures
using signal detection theory based on hit rates (HR), FA rates (FAR), accordingly:
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Responsivity index (RI) measured ‘tendency to respond’, where low numbers indicated a
conservative and high numbers indicated a liberal response strategy (Frey & Colliver, 1973;
Sahgal, 1987). d prime (primary outcome) is a standardized measure (denoted by “z”) of
sensitivity to appropriate responding. Accuracy (moving the joystick in the direction of the
target), RI, HR, omissions, FA, reaction time (RT), variability in RT, and PR were examined as
underlying drivers for performance (secondary outcomes).
2.3.2. Conners’ CPT-2
Participants were presented with letters (separated by an Inter-Stimulus Interval of 1, 2,
or 4 seconds) and instructed to use a keyboard to respond to all letters except “X”, where they
were instructed to withhold responses. Participants completed 18 blocks of 20 trials (total of 360
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trials). The non-target stimulus (“X”) appeared on 10% of trials. Target trials were a hit
(response) or omission (no response) and non-target trials were a false alarm (response) or
correct rejection (non-response). Response latencies were recorded. d prime measured sensitivity
to appropriate responding (primary outcome), while FA, omissions, and RT were examined as
drivers of performance (secondary outcomes). ADHD confidence index, a composite measure
that prospectively predicts ADHD diagnosis (Breaux et al., 2016), was also examined.
2.4. Statistical Analyses
Demographic, mental health, and substance use differences across HIV and METH
groups, ART use, nadir CD4 count, and VLS across PWH, and convergence between the 5C-
CPT and Conners’ CPT on d prime, omissions, and false alarms were evaluated via regressions.
Concurrent main (i.e., additive) and interactive (i.e., synergistic) effects of HIV and METH on
overall sustained attention (d prime) and drivers of performance (e.g., omissions, false alarms),
were examined via separate forced entry regressions. Drivers of performance were examined
regardless of d prime effects. Significant interactions were followed-up via ANOVA to examine
group differences. Mixed effects linear regressions examined main and interactive effects of HIV
and METH on vigilance, with performance split across three (5C-CPT) or six (Conners’ CPT)
blocks. A random intercept accounted for the repeated measures nature of the data, with trial
block, HIV, and METH modelled as fixed effects. Model fit was evaluated via -2 log likelihood
changes.
Continuous predictors were z-standardized and bootstrapping corrected for deviations
from normality. Regressions controlled for age, sex, education, and VLS, given their effects on
cognitive function (Heaton et al., 2015; Maki et al., 2018; Samson & Barnes, 2013; Satz et al.,
2011). A Bonferroni alpha correction for the greatest number of comparisons within a measure
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(i.e., eight comparisons in the secondary outcomes for the 5C-CPT, α = .05/8 = 0.006), was
applied to correct for family-wise error rate. No alpha correction was applied to d prime
analyses, given that it was the primary outcome. Data were analyzed using SPSS (v26.0).
3. Results
3.1. Data screening and group differences
Group differences are reported in Table 1. There were no significant HIVxMETH
interactions. METH+ subjects were younger (B=-3.974, SE=1.846, 95%CI[-7.583, -0.364]) and
less educated (B=-1.257, SE=0.345, 95%CI[-1.922, -0.573]), than METH- subjects. PWH were
more likely to be male (OR=0.075, 95%CI[0.015, 0.183]), than female. HIV+/METH+ subjects
did not differ from HIV+/METH- subjects on ART use (OR=0.747, 95%CI[0.221, 2.529]), or
nadir CD4 count (B=-45.552, 43.726, 95%CI[-127.586, 43.560]); however, HIV+/METH+ were
less likely to have VLS in plasma (i.e.,<50 copies of the virus per milliliter; OR=0.298,
95%CI[0.075, 0.768]). HIV+/METH+ subjects did not differ from HIV-/METH+ subjects on any
methamphetamine use characteristics. 5C-CPT d prime, omissions, and false alarms were
positively associated with Conners’ CPT d prime (B=0.062, SE=0.029, 95%CI[0.003, 0.113]),
omissions (B=8.891, SE=2.046, 95%CI[4.981, 12.601]), and false alarms (B=1.404, SE=3.805,
95%CI[1.062, 16.352]), respectively. Two participants (<1%) had missing data on VLS and were
excluded from analyses, resulting in a final analytical sample of N=203. 16 METH+ participants
had a positive urine toxicology screen for methamphetamine (UTOX(meth)+). Thus, analyses
were also run without UTOX(meth)+ participants.
3.2. Overall effects of HIV and METH on the 5C-CPT
There were no HIV effects on any outcome (Table 2 and Figure 1). METH+ was
associated with lower d prime. There were no other METH or HIVxMETH effects.
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3.2.1. 5C-CPT Analyses excluding participants with a positive urine toxicology screen
for methamphetamine
There were no significant main or interactive effects of METH or HIV on any outcomes
(Supplemental Table 1).
3.3. Effects of HIV and METH, aggregated across trial blocks on the 5C-CPT
The main effects model (Table 3 and Figure 2) had better fit, relative to a two-way
interaction model (Table 3), thus the three-way interaction model was not examined. There was a
significant effect of trial block on d prime, reflecting a vigilance decrement, driven by reduced
HR, and higher omissions. Responses also slowed across trials. There were no other significant
block effects. VLS was associated with higher d prime and more premature responses.
Controlling for VLS, PWH performed comparably on vigilance (d prime), but exhibited less
accuracy and slower RT, compared to HIV- participants. There were no other HIV effects.
METH+ was associated with worse vigilance (d prime), driven by lower HR and more
omissions. METH was not associated with accuracy or RT.
3.3.1. 5C-CPT by block analyses excluding participants with a positive urine
toxicology screen for methamphetamine
The main effects model (Supplemental Table 3) had better fit, relative to a two-way
interaction model (Supplemental Table 2). METH+ was not significantly associated with any
outcomes, while PWH had slower reaction time, compared to HIV- participants. HIV was not
significantly associated with accuracy after removing UTOX(meth)+ participants.
3.4. Overall effects of HIV and METH on Conners’ CPT
There were no significant effects of HIV or METH on any outcomes (see Table 5 and
Figure 3). There was a significant HIVxMETH interaction on ADHD confidence index (prior to
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Bonferroni adjustment), whereby HIV-/METH+ (M=67.750, SE=3.205) participants had a higher
ADHD confidence index than HIV-/METH- (M=54.142, SE=2.335) participants
(Meandiff=13.608, SE=3.879, 95%CI[6.044, 22.167]). There was no significant difference
between HIV+/METH+ (M=62.938, SE=2.780) and HIV+/METH- (M=59.939, SE=2.647) on
ADHD confidence index (Meandiff=2.998, SE=3.555, 95%CI[-4.410, 9.749]). There were no
other significant HIVxMETH effects.
3.4.1. Conners’ CPT Analyses excluding participants with a positive urine toxicology
screen for methamphetamine
There were no significant main effects of METH+ or HIV on any outcome variables.
There was a significant HIVxMETH interaction on ADHD confidence index (prior to Bonferroni
adjustment). HIV-/METH+ (M=65.472, SE=1.309) participants had a higher ADHD confidence
index than HIV-/METH- (M=54.459, SE=0.899) participants (Meandiff=11.013, SE=1.693,
95%CI[7.634, 14.340]). There was no significant difference between HIV+/METH+ (M=59.390,
SE=1.198) and HIV+/METH- (M=60.575, SE=1.034) on ADHD confidence index (Meandiff=-
1.185, SE=1.425, 95%CI[-3.945, 1.681]; Supplemental Table 4).
3.5. Effects of HIV and METH, aggregated across trial blocks on Conners’ CPT
The main effects model (Table 7 and Figure 4) had better fit, relative to a two-way
interaction model (see Table 6), thus the three-way interaction model was not examined.
Omissions, FAs, and RT error significantly increased across blocks, while RT remained stable.
VLS was associated with less omissions. Controlling for VLS, HIV was only associated with
slower RT. METH+ participants had more omissions, RT error, and slower reaction time,
relative to METH- participants. METH+ was not associated with FA.
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3.5.1. Conners’ CPT by block analyses excluding participants with a positive urine
toxicology screen for methamphetamine
The main effects model (Supplemental Table 6) had better fit than a two-way interaction
model (Supplemental Table 5). METH+ was not significantly associated with any outcomes.
HIV+ was only associated with slower RT.
4. Discussion
This study examined the additive versus synergistic effects of HIV and METH on
sustained attention and vigilance. METH+, but not HIV, was associated with sustained attention
and vigilance deficits, after controlling for VLS, suggesting a lack of additive HIV effect. There
was no synergistic effect of HIV and METH. METH+ was associated with poorer sustained
attention and vigilance, driven by lower hit rate (5C-CPT) and more target omissions (5C-CPT
and Conners’ CPT). METH+ was also associated with slower reaction time and greater reaction
time error (Conners’ CPT). The main effects of METH+ on sustained attention and vigilance
disappeared after removing UTOX(meth)+ participants, highlighting the role of recent METH in
this relationship.
Contrary to hypotheses, PWH did not have worse sustained attention and vigilance
relative to HIV- participants, displaying only a decrement in accuracy, which disappeared after
removing UTOX(meth)+ participants. PWH displayed reaction time slowing (both CPTs), which
persisted after removing UTOX(meth)+ participants. Contrary to hypotheses, there was no
HIVxMETH+ interaction on sustained attention and vigilance. However, there was a significant
HIVxMETH interaction on ADHD confidence index. HIV-/METH+ participants had a higher
ADHD confidence index, relative to HIV-/METH- participants (prior to Bonferroni correction),
even after removing UTOX(meth)+ participants.
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Recent METH use among METH+ people, rather than METH+ alone, was associated
with sustained attention and vigilance deficits. This result extends Levine et al. (2006),
highlighting sustained attention and vigilance deficits with recent stimulant use, irrespective of
HIV. Results also extend Basterfield et al. (2019), who found rebound effects for certain
cognitive domains among recently abstinent METH+ people. Further research should examine
what aspect of recent use (acute intoxication, dosage, residual effects, or withdrawal) is
associated with impairment and the direction of this relationship. Namely, whether METH+
people with greater sustained attention and vigilance deficits are likely to have used METH
recently (e.g., as an attempt to self-medicate attentional or other problems), or whether recent
METH use among METH+ people confers sustained attention and vigilance deficits. These
studies are important given that amphetamine administration in healthy participants improves
5C-CPT performance in humans, mice (MacQueen, Minassian, Kenton et al, 2018), and rats
(Young et al, 2020). Chronicity of METH use may obviate the benefits of acute effects.
Although the lack of METH+ effects after removing UTOX(meth)+ participants are at
odds with Potvin et al., (2018), it should be noted that the studies included in that meta-analysis
differed on participant METH use recency. Some studies required participants to be
UTOX(meth)+ during cognitive testing, whereas others included recently abstinent METH+
participants. Since Potvin et al., (2018) did not control for METH use recency, it is not possible
to disentangle whether METH+ alone, or recent METH use among METH+ people (as found in
this study), affected cognitive function.
Several reasons may account for the lack of synergistic HIV and METH effect on
sustained attention and vigilance. METH+ may not have necessarily pre-dated HIV
seroconversion. Thus, HIV diagnosis (and ART initiation) may not have been delayed, sparing
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this group from enduring brain injury and cognitive impairment. This notion is supported by
Montoya et al. (2016) who found 20% of HIV+/METH+ persons initiated METH use following
HIV diagnosis. Alternatively, the lack of synergistic HIVxMETH effects may indicate that
HIV+/METH+ are no more susceptible than HIV+/METH- to early immunosuppression (leading
to enduring cognitive impairment). Indeed, our results found no difference in nadir CD4 count
between the HIV+/METH- and HIV+/METH+ groups. However, it is unclear whether these
similar nadir CD4 counts are attributable to HIV diagnosis predating METH+ onset, or whether
HIV+/METH+ persons are truly no more susceptible to early immunosuppression, than
HIV+/METH- individuals. Further research is required.
Nonetheless, there was a HIVxMETH interaction on Conners’ CPT. HIV-/METH+
participants had a higher ADHD confidence index, than HIV-/METH- participants, a group
difference not found using the DIS for DSM-IV, which relies on self-report of symptoms. This
discrepancy may underscore the sensitivity of Conners’ CPT ADHD confidence index in
capturing the elevated rates of ADHD among METH users, noted in previous studies (Bordoloi,
Chandrashekar, & Yarasi, 2019) and observed in our HIV-/METH+ group. Further research
should aim to replicate these results, which were not significant following Bonferroni correction
and thus, should be interpreted with caution.
HIV was only consistently associated with psychomotor slowing. This finding may
indicate that while an impairment in reaction time is still detectable, the current sample of PWH
had lower levels of cognitive impairment, than found in previous, virally suppressed PWH
(Sanford et al., 2018). The discrepancy in findings may be attributable to the generally high nadir
CD4 counts across both HIV+ groups in the current study, reflecting on average, the absence of
previous immunosuppression. Alternatively, these results may be attributable to the fact that
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while untreated HIV has an irreversible, detrimental impact on psychomotor and some cognitive
functions (Muñoz-Moreno et al., 2008), sustained attention and vigilance may be spared from
enduring deficits. Current results may also indicate that while ART has pro-cognitive effects on
some cognitive domains, it has little effect on psychomotor function, the most prominent deficit
associated with advanced HIV (i.e., acquired immunodeficiency syndrome; Reger et al., 2002).
Both notions are supported by Eggers et al. (2017) who posited psychomotor slowing to be a
salient feature of HAND, despite VLS. Alternatively, psychomotor slowing may be indicative of
a speed/ accuracy trade-off, whereby PWH compensate for cognitive impairment by slowing
responding to prioritize accuracy, as found previously (Kronemer et al., 2017). Animal models
are well-positioned to further test these hypotheses.
4.1. Implications
Current and previous findings highlight the importance of VLS in cognitive function
among PWH (Heaton et al., 2015), reiterating the need for prompt HIV diagnosis and ART
initiation (and maintenance). Routine opt-out screening may be a cost-effective means of
increasing prompt HIV diagnosis (Krueger et al., 2019; Sanders et al., 2005). Peer-to-peer social
support increases ART adherence among substance-using and non-using PWH (Horvath et al.,
2013; Hosek et al., 2018; Kerrigan et al., 2018). Given that sustained attention and vigilance
deficits were less pronounced in recently abstinent METH+, clinicians should treat METH+ to
halt cognitive impairment associated with recurrent use. Cognitive behavioral therapy and
contingency management have some efficacy in treating METH+ (Lee & Rawson, 2008;
Rawson et al., 2006; Roll, 2007). Such suggestions, while not novel, are strongly supported by
the current data.
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Current results have implications for the assessment of sustained attention and vigilance.
Significant associations were observed between the 5-Choice and Conners’ CPTs. Both CPTs
captured vigilance deficits seen in METH+ persons and slowed reaction time seen in PWH.
These findings reiterate the validity and provide further psychometric support for 5C-CPT as a
measure of sustained attention and vigilance among PWH and METH+ persons. Using 5C-CPT
allows for comparisons with future animal research aimed at delineating mechanisms
underpinning the deficits seen in this study.
4.2. Strengths and limitations
We controlled for age, sex, education, and VLS, which are associated with cognitive
function (Heaton et al., 2015; Maki et al., 2018; Samson & Barnes, 2013; Satz et al., 2011). We
excluded people with current substance dependence (excluding nicotine), a history of head
injuries, medical, psychotic, or neurological conditions known to impact cognitive function
(Cunha et al., 2013; Perry et al., 2008; Senathi-Raja et al., 2010; Stavro et al., 2013). Thus,
participant performance was unlikely confounded by these factors. Another strength was the use
of a urine toxicology screen, which allowed us to examine the effects of METH+ on sustained
attention and vigilance, with and without UTOX(meth)+ people.
This study has some limitations. Although we controlled for education, this reflects only
one factor of a multifaceted cognitive reserve construct, which buffers against HAND in PWH
(Morgan et al., 2012). We did not control for smoking, which has some pro-cognitive effects
(Majdi et al., 2019). Although expected, our sample was predominantly male (95%), limiting the
generalizability of results to females with HIV. Given the known sex differences in cognitive
function among PWH (Heaton et al., 2015; Maki et al., 2018), future research could examine
potential three-way interactions between HIV, METH, and sex, within a more representative
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (whichthis version posted June 4, 2020. . https://doi.org/10.1101/2020.06.03.132522doi: bioRxiv preprint
17
sample, controlling for cognitive reserve and smoking. Such studies can also be conducted in
rodents. Finally, a majority of nadir CD4 values in the present study were self-reported (n = 96,
94%, versus n = 6, 6% derived from lab values). Given the known memory deficits associated
with HIV (Walker & Brown, 2018), the reliability of the nadir CD4 variable in this study is
questionable. Future research should obtain information regarding nadir CD4 from more
objective sources.
5. Conclusions
Controlling for VLS, which was associated with better vigilance, PWH did not exhibit
sustained attention and vigilance deficits, but rather, exhibited only psychomotor slowing.
Further research should examine whether psychomotor slowing reflects pervasive deficits despite
VLS, or an adaptive, speed/ accuracy trade-off. METH+ was associated with deficits in sustained
attention and vigilance. This effect was no longer significant after removing recent
methamphetamine users, potentially suggesting a sustained attention and vigilance rebound
among METH+ people, following abstinence. Further research should examine the direction of
this relationship and identify the aspects of recent use (e.g., acute intoxication, residual effects,
or withdrawal) that are associated with deficits. These effects can be tested directly in animals.
There were no synergistic HIV by METH effects on sustained attention and vigilance.
Longitudinal research should examine whether onset of METH+ prior to HIV seroconversion is
associated with worse cognitive outcomes. The 5C-CPT was found to be an appropriate measure
of sustained attention and vigilance deficits in PWH and METH+ people. Using the 5C-CPT
enables future comparisons with rodent research examining the underlying mechanisms driving
deficits found in this study. Ultimately, results underscore the need for prompt HIV diagnosis
and ART initiation, and treatment of METH+ to preserve cognitive function.
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (whichthis version posted June 4, 2020. . https://doi.org/10.1101/2020.06.03.132522doi: bioRxiv preprint
18
Funding Sources/Acknowledgments
This study was supported by P50 DA26306 and R01DA043535. Nina Pocuca is also supported
by an Interdisciplinary Research Fellowship in NeuroAIDS (IRFN; R25MH081482). We
acknowledge Nathan Wood for his contribution to the project.
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was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (whichthis version posted June 4, 2020. . https://doi.org/10.1101/2020.06.03.132522doi: bioRxiv preprint